Flavonoid-Containing Compositions and Treatment of Viral Diseases with Same

Priority is hereby claimed to U.S. Provisional Application 63/659,539, filed Jun. 13, 2024, which is incorporated herein by reference in its entirety.

The invention is directed to compositions that contain flavonoids such as hesperidin, quercetin, hesperetin, and rutin and methods of treating viral diseases such as coronavirus (e.g., SARS COV-2) infection, virus infection, rhinovirus infection, and human metapneumovirus infection.

Compositions and methods for treating viral diseases such as coronavirus (e.g., SARS CoV-2) infection, virus infection, rhinovirus infection, and human metapneumovirus with efficacious combinations of flavonoids are needed.

One aspect of the invention is directed to compositions. In some versions, the compositions comprise active agents and a carrier, wherein the active agents comprise a first set of flavonoids, wherein the first set of flavonoids consist of: hesperidin; quercetin; and hesperetin, rutin, or a combination of hesperetin and rutin.

In some versions, the composition does not contain at least one of naringin, naringenin, diosmin, quercetin, nobiletin, and tangeretin in an amount more than 1% w/w of the combined mass of the first set of flavonoids.

In some versions, the composition does not contain any one of naringin, naringenin, diosmin, quercetin, nobiletin, and tangeretin in an amount more than 1% w/w of the combined mass of the first set of flavonoids.

In some versions, the composition does not contain any flavonoid other than the flavonoids in the first set of flavonoids in an amount more than 1% w/w of the combined mass of the first set of flavonoids.

In some versions, the first set of flavonoids consists of: hesperidin; quercetin; and rutin or a combination of rutin and hesperetin, and wherein the hesperidin and the rutin are provided in the composition in amounts effective to synergize binding of at least one of the hesperidin and the rutin to SARS-COV-2 spike protein.

In some versions, the first set of flavonoids consists of hesperidin, quercetin, and rutin.

In some versions, the first set of flavonoids consists of hesperidin, quercetin, and hesperetin.

In some versions, the active ingredients further comprise one or more of piperine, a zinc salt, vitamin C, vitamin D3, N-acetylcysteine, and an omega-3 fatty acid.

In some versions, the active ingredients comprise: hesperidin; quercetin; hesperetin, rutin, or a combination of hesperetin and rutin; piperine; a zinc salt; vitamin C; vitamin D3; N-acetylcysteine; and, optionally, one or more omega-3 fatty acids. In some versions, the active ingredients comprise: hesperidin; quercetin; hesperetin; piperine; a zinc salt; vitamin C; vitamin D3; and N-acetylcysteine. In some versions, the active ingredients comprise: hesperidin; quercetin; rutin; piperine; a zinc salt; vitamin C; vitamin D3; N-acetylcysteine; and one or more omega-3 fatty acids.

In some versions, the active ingredients consist of: hesperidin; quercetin; hesperetin, rutin, or a combination of hesperetin and rutin; piperine; a zinc salt; vitamin C; vitamin D3; N-acetylcysteine; and, optionally, one or more omega-3 fatty acids. In some versions, the active ingredients consist of: hesperidin; quercetin; hesperetin; piperine; a zinc salt; vitamin C; vitamin D3; and N-acetylcysteine. In some versions, the active ingredients consist of: hesperidin; quercetin; rutin; piperine; a zinc salt; vitamin C; vitamin D3; N-acetylcysteine; and one or more omega-3 fatty acids.

In some versions, the active ingredients comprise: hesperidin in an amount from 150 mg to 600 mg; quercetin in an amount from 150 mg to 700 mg; hesperetin in an amount from 1 mg to 120 mg, rutin in an amount from 150 mg to 600 mg, or a combination of hesperetin in an amount from 1 mg to 120 mg and rutin in an amount from 150 mg to 600 mg; piperine in an amount from 1 mg to 50 mg; a zinc salt in an amount from 1 mg to 25 mg; vitamin C in an amount from 1 mg to 50 mg; vitamin D3 in an amount from 60 IU to 650 IU; N-acetylcysteine in an amount from 100 mg to 500 mg; and optionally, one or more omega-3 fatty acids in a total amount from 150 mg to 600 mg.

In some versions, the active ingredients consist of: hesperidin in an amount from 150 mg to 600 mg; quercetin in an amount from 150-700 mg; hesperetin in an amount from 1 mg to 120 mg, rutin in an amount from 150 mg to 600 mg, or a combination of hesperetin in an amount from 1 mg to 120 mg and rutin in an amount from 150 mg to 600 mg; piperine in an amount from 1 mg to 50 mg; a zinc salt in an amount from 1 mg to 25 mg; vitamin C in an amount from 1 mg to 50 mg; vitamin D3 in an amount from 60 IU to 650 IU; N-acetylcysteine in an amount from 100 mg to 500 mg; and optionally, one or more omega-3 fatty acids in a total amount from 150 mg to 600 mg.

In some versions, the composition is in a form of a capsule or a gel cap.

Another aspect of the invention is directed to methods of treating a viral infection in a subject. The methods can comprise administering a composition of the invention to the subject in an amount effective to treat the viral infection. In some versions, the infection is selected from the group consisting of a coronavirus infection, an influenza virus infection, a rhinovirus infection, and a human metapneumovirus infection.

The objects and advantages of the invention will appear more fully from the following detailed description of the preferred embodiment of the invention made in conjunction with the accompanying drawings.

On aspect of the invention is directed to compositions comprising active agents. The active agents of the invention preferably comprise flavonoids. The flavonoids preferably comprise various combinations of hesperidin, quercetin, hesperetin, and rutin. The structure of hesperidin is:

The structure of quercetin is:

The structure of hesperetin is:

The structure of rutin is:

The hesperidin, quercetin, hesperetin, and/or rutin can be considered to form a first set of flavonoids that consist of: hesperidin; quercetin; and hesperetin, rutin, or a combination of hesperetin and rutin. In some versions, the first set of flavonoids consists of hesperidin; quercetin; hesperetin, rutin, or a combination of hesperetin and rutin; and neohesperidin. The structure of neohesperidin is:

In some versions, the compositions of the invention include hesperidin in an amount from 25 mg to 5,000 mg, such as from 85 mg to 1,500 mg, about 250 mg, or about 250 mg to about 500 mg. In some versions, the compositions of the invention include hesperidin in an amount from 150 mg to about 600 mg.

In some versions, the compositions of the invention include quercetin in an amount from 25 mg to 5,000 mg, such as from 85 mg to 1,500 mg, about 250 mg, or about 400 mg to about 600 mg. In some versions, the compositions of the invention include quercetin in an amount from 150 mg to about 700 mg.

In some versions, the compositions of the invention include hesperidin in an amount from 6 mg to 650 mg, such as from 20 mg to 200 mg, or about 65 mg. In some versions, the compositions of the invention include hesperidin in an amount from 1 about mg to about 120 mg.

In some versions, the compositions of the invention include rutin in an amount from 25 mg to 5,000 mg, such as from 85 mg to 1,500 mg, about 250 mg, or about 250 mg to about 500 mg. In some versions, the compositions of the invention include rutin in an amount from 150 mg to about 600 mg.

The flavonoids in the first set of flavonoids are preferably included in the composition in a purified form such that one or more flavonoids that may normally present with them are not included in the composition.

In various versions of the invention, for example, the composition does not contain at least one of naringin, naringenin, diosmin, nobiletin, and tangeretin in an amount more than 25% w/w, 20%, w/w, 15%, w/w, 10% w/w, 5% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, 0.01% w/w, 0.005% w/w, or 0.001% w/w of the combined mass of the first set of flavonoids. In some versions of the invention, the composition is completely devoid of at least one of naringin, naringenin, diosmin, nobiletin, and tangeretin.

In various versions of the invention, the composition does not contain any one of naringin, naringenin, diosmin, nobiletin, and tangeretin in an amount more than 25% w/w, 20%, w/w, 15%, w/w, 10% w/w, 5% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, 0.01% w/w, 0.005% w/w, or 0.001% w/w of the combined mass of the first set of flavonoids. In some versions, of the invention, the composition is completely devoid of each of naringin, naringenin, diosmin, nobiletin, and tangeretin.

In various versions of the invention, the composition does not contain any one or more flavonoids shown inother than the flavonoids of the first set of flavonoids in an amount more than 25% w/w, 20%, w/w, 15%, w/w, 10% w/w, 5% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, 0.01% w/w, 0.005% w/w, or 0.001% w/w of the combined mass of the first set of flavonoids. In some versions of the invention, the composition is completely devoid of any one or more flavonoids shown inother than the flavonoids of the first set of flavonoids.

In various versions of the invention, the composition does not contain any flavonoids shown inother than the flavonoids of the first set of flavonoids in an amount more than 25% w/w, 20%, w/w, 15%, w/w, 10% w/w, 5% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, 0.01% w/w, 0.005% w/w, or 0.001% w/w of the combined mass of the first set of flavonoids. In some versions of the invention, the composition is completely devoid of each of the flavonoids shown inother than the flavonoids of the first set of flavonoids.

In various versions of the invention, the composition does not contain any flavonoid other than the flavonoids of the first set of flavonoids in an amount more than 25% w/w, 20%, w/w, 15%, w/w, 10% w/w, 5% w/w, 1% w/w, 0.5% w/w, 0.1% w/w, 0.05% w/w, 0.01% w/w, 0.005% w/w, or 0.001% w/w of the combined mass of the first set of flavonoids. In some versions of the invention, the composition is completely devoid of any flavonoid other than the flavonoids of the first set of flavonoids.

As used herein, the term “flavonoid” refers to compounds have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and a heterocyclic ring (C, the ring containing the embedded oxygen). This carbon structure can be abbreviated C6-C3-C6. According to the IUPAC nomenclature. An exemplary flavonoid carbon skeleton is as follows:

Exemplary flavonoids and types of flavonoids are provided in.

As shown in the following examples hesperidin and rutin can synergize their binding to certain proteins, such as the SARS-COV-2 spike protein. Accordingly, some versions of the invention include the hesperidin and the rutin in the composition in amounts effective to synergize binding of at least one of the hesperidin and the rutin to SARS-COV-2 spike protein.

In some versions, the compositions of the invention can comprise any one or more flavonoids shown or predicted (e.g., via in silico analysis) in the following examples as binding any one or more of the SARS-COV-2 spike protein, SARS-COV-2 TMPRSS2, influenza virus haemagglutinin, rhinovirus VP1 antigen, ICAM1, human metapneumovirus F protein, human metapneumovirus G protein, and human metapneumovirus IFG-1R.

The compositions of the invention can comprise other active agents other than flavonoids. Such active agents can include, for example, any one or more of piperine, zinc, vitamin C, vitamin D3, N-acetylcysteine, and one or more omega-3 fatty acids.

In some versions, the compositions of the invention comprise piperine. The piperine can be included in the compositions in the form of BIOPERINE® (Sabinsa Corporation, East Windsor, NJ). In some versions, the piperine is included in the composition in an amount from 0.5 mg to 100 mg, such as from 2 mg to 30 mg, about 5 mg, or from about 5 mg to about 10 mg. In some versions, the piperine is included in the composition in an amount from 1 mg to 50 mg.

In some versions, the composition comprises zinc. The zinc can be in the form of a zinc salt, such as zinc citrate. In some versions, the zinc salt is included in the composition in an amount from 1.5 mg to 150 mg, such as from 5 mg to 50 mg or about 15 mg. In some versions, the zinc salt is included in the composition in an amount from 1 mg to 50 mg or from 1 mg to 25 mg.

In some versions, the composition comprises vitamin C (ascorbic acid). In some versions, the vitamin C is included in the composition in an amount from 3 mg to 300 mg, such as from 10 mg to 100 mg or about 30 mg. In some versions, the vitamin C is included in the composition in an amount from 1 mg to 50 mg.

In some versions, the composition comprises vitamin D3 (cholecalciferol). In some versions, the vitamin D3 is included in the composition in an amount from 20 International Units (IU) μg to 2,000 IU, such as 60 IU to 650 IU, or about 200 IU.

In some versions, the composition comprises N-acetylcysteine. In some versions, the N-acetylcysteine is included in the composition in an amount from 20 mg to 4,000 mg, such as from 60 mg to 1,200 mg, about 300 mg, or from about 200 mg to about 400 mg. In some versions, the N-acetylcysteine is included in the composition in an amount from 100 mg to 500 mg.

In some versions, the composition comprises one or more omega-3 fatty acids. The omega-3 fatty acids can comprise eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or a combination thereof, among others. In some versions, the omega-3 fatty acids are included in the composition in an amount from 25 mg to 5,000 mg, such as from 85 mg to 1,500 mg, about 250 mg, or about 250 mg to about 500 mg. In some versions, the omega-3 fatty acids are included in the composition in an amount from 150 mg to about 600 mg.